JPS628116B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel thiocarbostyryl derivatives. The thiocarbostyryl derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula [1]. [In the formula, R is a hydrogen atom or a lower alkyl group, Y
each represents a lower alkylene group. ] The compound of the present invention has an antihistamine effect and a central nervous system depressant effect, and therefore can be used as an antihistamine agent for allergic symptoms of the respiratory respiratory tract such as combing, nasal discharge, itching of the eyes, nose, and throat, hay fever, hay fever, acute It is useful as a therapeutic and preventive agent for hives, angioedema, pruritus, allergic rhinitis, etc., and as a central nervous system depressant, such as a central muscle relaxant,
It is useful as a sleep-inducing drug, a pre-surgery drug, an anti-schizophrenic drug, a drug for treating neurosis and psychosomatic disorders, an antipyretic analgesic, a sedative, an anti-manic drug, etc. In this specification, examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl groups.
Examples of lower alkylene groups include methylene,
Ethylene, trimethylene, 2-methyltrimethylene, 1-methyltrimethylene, tetramethylene,
Examples include pentamethylene, hexamethylene, 2-ethylethylene, and 2,2-dimethyltrimethylene groups. Representative compounds of the present invention are listed below. Γ 7-[3-(4-phenyl-1-piperazinyl)propoxy]thiocarbostyryl Γ 5-[3-(4-phenyl-1-piperazinyl)propoxy]thiocarbostyryl Γ 6-[3-(4-phenyl) -1-piperazinyl)propoxy]thiocarbostyryl Γ 8-[3-(4-phenyl-1-piperazinyl)propoxy]thiocarbostyryl Γ 4-methyl-7-[3-(4-phenyl-1-
piperazinyl)propoxy]thiocarbostyryl Γ 4-methyl-5-[3-(4-phenyl-1-
piperazinyl) propoxy]thiocarbostyryl Γ 4-ethyl-6-[3-(4-phenyl-1-
Piperazinyl)propoxy]thiocarbostyryl Γ 5-[2-(4-phenyl-1-piperazinyl)propoxy]thiocarbostyryl Γ 7-[4-(4-phenyl-1-piperazinyl)propoxy]thiocarbostyryl Γ 7- [2-methyl-3-(4-phenyl-1-
Piperazinyl)propoxy]thiocarbostyryl Γ 5-[6-(4-phenyl-1-piperazinyl)hexyloxy]thiocarbostyryl The compound of the present invention can be produced by various methods, but a preferred example thereof is as follows. It is produced by the method shown in Reaction Scheme-1. [In the above formula, X ¹ , X ² and X represent halogen atoms. R and Y are the same as above. ] In Reaction Scheme-1, the reaction between the compound represented by the general formula [2] and the compound represented by the general formula [3] is carried out using a basic compound as a dehydrohalogenation agent in an appropriate solvent at room temperature to 200°C. Preferably 50-150
It is carried out within a few hours to 15 hours at ℃. In the above, suitable solvents include, for example, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane, diethylene glycol, and dimethyl ether, and aromatic hydrocarbons such as benzene, toluene, and xylene. , dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like. Basic compounds that can be used as dehydrohalogenation agents include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, metallic potassium, sodium Examples include tertiary amines such as amide, pyridine, quinoline, triethylamine, and tripropylamine. In the above reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide can also be used as a reaction promoter. The ratio of the compound represented by the general formula [2] and the compound represented by the general formula [3] is not particularly limited, but the latter is usually 1 to 5 moles per 1 mole of the former, preferably 1 to 1.2 moles. It is best to use a molar amount. The reaction between the compound represented by the general formula [4] and the compound represented by the formula [5] is carried out in the absence of a solvent or in a common inert solvent at room temperature to 200°C, preferably at 60 to 120°C.
The process is completed within several hours to 24 hours at a temperature of ℃. As the inert solvent, the lower alcohols mentioned above,
Any of the above-mentioned ethers, the above-mentioned aromatic hydrocarbons, polar solvents such as dimethylformamide, dimethyl sulfoxide, etc. can be used. The above reaction is more advantageously carried out using a basic compound as dehydrohalogenating agent. As the basic compound, for example, tertiary amines such as calcium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, and quinoline can be used. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary. The ratio of the compound represented by the general formula [4] and the compound represented by the formula [5] in the above reaction is usually at least 1 mole of the former, preferably 1 to 5 times the mole of the latter, more preferably 1 mole or more of the latter.
It should be ~1.2 times the mole. The reaction between the compound represented by the general formula [6] and the compound represented by the general formula [7] is carried out in the absence of a solvent or in a suitable inert solvent, usually at a temperature of 50 to 150°C, preferably 80 to 110°C. It will be completed in about 3 to 8 hours. Examples of the inert solvent include the above-mentioned ethers, the above-mentioned aromatic hydrocarbons, dimethyl sulfoxide, dimethylformamide, and the like. As for the ratio of the compound of general formula [6] and the compound of general formula [7], when the reaction is carried out without a solvent, it is usually best to use a large excess amount of the latter relative to the former; When the reaction is carried out, the latter is usually used in an equimolar amount or more, preferably 1 to 3 times the molar amount of the former. Compound of general formula [8] and thiourea

The reaction with [9] is completed in about 3 to 8 hours in a suitable inert solvent at a temperature of usually 50 to 150°C, preferably 50 to 80°C. Examples of the inert solvent used include the lower alcohols, the ethers, the aromatic hydrocarbons, dimethyl sulfoxide, and dimethylformamide. The ratio of the compound of general formula [8] and thiourea to be used is usually at least an equimolar amount of the latter, preferably about 3 to 8 times the molar amount of the former. The reaction is preferably carried out under a gas flow of nitrogen, argon gas, etc., ie, in the absence of oxygen, so that the by-product of disulfide can be suppressed. Thus, the general formula [1]
The compound of the present invention represented by is obtained. The compound of the present invention represented by the general formula [1] can also be produced by reacting the compound of the general formula [6] with phosphorus pentasulfide [10]. The reaction is completed in about 3 to 8 hours in the presence of a dehydrohalogenating agent in a suitable inert solvent at a temperature of usually 50 to 150°C, preferably 80 to 120°C. The ratio of the compound of general formula [6] and phosphorus pentasulfide to be used is usually at least an equimolar amount of the former, preferably an equimolar to twice the molar amount of the latter. Examples of dehydrohalogenation agents include tertiary amines such as pyridine, quinoline, and tripropylamine, and examples of inert solvents include aromatic hydrocarbons, dimethyl sulfoxide, and dimethylformamide. The reaction is preferably carried out under a gas flow of nitrogen, argon gas, etc., ie, in the absence of oxygen, so that the by-product of disulfide can be suppressed. The thiocarbostyryl derivative represented by the general formula [1] obtained above can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid, and such salts are also included in the compounds of the present invention. be done. Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid,
Mention may be made of inorganic acids such as hydrobromic acid, and organic acids such as acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methanesulfonic acid, and benzoic acid. The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, and the like. Incidentally, the present invention naturally also includes optical isomers. When the compound of general formula [1] and its salt are used for the therapeutic purpose of the present invention, they are usually put into the form of a pharmaceutical composition together with a pharmaceutical carrier. Carriers include fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, diluents, excipients, etc. that are commonly used to prepare drugs according to the usage form. It can be prepared by a conventional method using Various dosage unit forms can be selected depending on the therapeutic purpose; typical examples include tablets,
Examples include pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments, and the like. The amount of the compound of general formula [1] to be contained in the above formulation is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight based on the total composition. Furthermore, there are no particular restrictions on the use of the above-mentioned preparations, and they can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids. If necessary, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it can be administered rectally; and in the case of an ointment, it can be applied. The dosage of the preparation is appropriately selected depending on the purpose of use, symptoms, etc., and usually the compound of general formula [1] is
A pharmaceutical composition containing about 40 μg to 2 mg/Kg·day may be administered in 3 to 4 divided doses. Pharmacological Test A method using isolated guinea pig ileum is generally accepted as a typical method for measuring antihistamine action in vitro, and the present invention also uses this method to measure antihistamine action in vitro. Antihistamine effect was measured. Antihistamine effect test Male guinea pigs weighing 300 to 500 g were killed by exsanguination, and the ileum 15 cm proximal to the ileocecal region was removed and treated with Tyrode's solution (NaCl 8.0 g, KCl 0.2 g, CaCl ₂ 0.2 g, glucose 1.0 g, NaHCO ₃ 1.0g, NaH ₂ PO ₄・
Water was added to 0.065 g of 2H ₂ O and 0.2135 g of MgCl ₂ .6H ₂ O to make a total volume of 1000 ml). The tissue was then cut into 2.5-3.0 cm pieces and suspended in a bath filled with 30 ml of Tyrode's solution. The bath was kept at 36° C. and passed through a gas mixture of 5% CO ₂ and 95% O ₂ . After 10 minutes, 10 ^{-6 M} of histamine was administered to examine tissue sensitivity, and a dose-response curve (control) using histamine was obtained. After the control dose-response had stabilized, 10 ^-6 g/ml of the test compound was administered, and 5 minutes later histamine was administered to obtain a dose-response curve. Contraction is performed using an isotonic transducer [Nihon Kohden TD-
112S] and recorded on a pen recorder. The maximum contraction of control histamine was taken as 100%, and Van Rossam's method [JMVan Rossam,
Arch.Int.Pharmacodyn. 143 , 299 (1963)]
PA ₂ was calculated according to the following. The results obtained are shown in Table 1 for each test compound below.

[Table] Reference examples and examples are listed below. Reference Example 1 16.1 g of 7-hydroxycarbostyryl and 9 g of potassium hydroxide are mixed in 150 ml of isopropanol, stirred at 70-80°C for 30 minutes, then 25 g of 1,3-bromochloropropane is added and heated under reflux for 6 hours. After the reaction is complete, pour the reaction solution into 200 ml of 2N aqueous sodium hydroxide solution, remove insoluble matter, wash with water and dry. The crude crystals were recrystallized from ethanol to obtain 18.2 g of 7-(3-chloropropoxy) carbostyril in the form of yellow needles. Melting point 130-133℃ Reference example 2 7-(3-chloropropoxy)carbostyryl
4.8g and 4g of phenylpiperazine in toluene 40g
ml and heated under reflux for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in 80 ml of chloroform.
The chloroform layer is washed twice with a 5.0% aqueous sodium bicarbonate solution and then twice with water, dried over anhydrous sodium sulfate, and then the chloroform is distilled off. The residue was recrystallized from methanol to give yellow needles of 7-
3.2 g of [3-(4-phenyl-1-piperazinyl)propoxy]carbostyryl are obtained. Melting point 237-238℃ Reference example 3 7-[3-(4-phenyl-1-piperazinyl)
Propoxy] carbostyril 2g with phosphorus oxychloride
The mixture was mixed with 30 ml of water, heated under reflux for 7 hours, concentrated under reduced pressure, and 80 ml of water was added to the residue, which was left overnight. When the precipitate was washed with water and recrystallized from ethanol, yellow needle-like crystals of 2-chloro-7-[3-(4-phenyl-1-piperazinyl)propoxy]-quinoline were obtained.
1.5g is obtained. Melting point 206-208°C Example 1 2-chloro-7-[3-(4-phenyl-1-piperazinyl)propoxy]quinoline under nitrogen flow
1.5 g and 2.0 g of thiourea in dimethylformamide
After stirring for 5 hours at 60-70℃, add 5% to the residue after distilling off dimethylformamide under reduced pressure.
Add 50 ml of % sodium bicarbonate aqueous solution and extract the organic acid with chloroform. After washing the chloroform layer with water and dehydrating it, the residue after distilling off the chloroform was recrystallized from benzene-chloroform to give yellow needle-like crystals of 7-[3-(4-phenyl-1-piperazinyl).
Propoxy]thiocarbostyryl hemihydrate
0.8g obtained. Melting point: 213-215°C Compounds of Examples 2 and 3 are obtained in the same manner as in Example 1 using appropriate starting materials. Example 2 6-[3-(4-phenyl-1-piperazinyl)
Propoxy]thiocarbostyryl Pale yellow needle crystals (recrystallization solvent: chloroform-benzene) Melting point 201-203°C Example 3 4-Methyl-7-[3-(4-phenyl-1-piperazinyl)propoxy]thiocarbostyryl・
1/2H ₂ O Yellow needle crystals (recrystallization solvent: chloroform-benzene) Melting point 225-227°C Example 4 7-[3-(4-phenyl-1-piperazinyl)
Propoxy] carbostyryl 1.8g, phosphorus pentasulfide 1.0
g and 1 ml of pyridine were mixed in 50 ml of toluene, and the mixture was heated under reflux for 5 hours under an argon atmosphere. The reaction solution is concentrated under reduced pressure to remove about 40 ml of toluene, and then 80 ml of chloroform is added and filtered. The mother liquor is washed with water, dehydrated, and the chloroform is distilled off. The residue was separated by silica gel column chromatography and recrystallized from benzene-chloroform to yield 7-[3-(4-phenyl-1-piperazinyl)propoxy]thiocarbostyryl 1/2 as yellow needle-shaped crystals with a melting point of 212-214°C.
0.4 g of hydrate is obtained.

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydrogen atom or a lower alkyl group, Y
each represents a lower alkylene group. ] A thiocarbostyryl derivative represented by these and its salt.